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WO2022145989A1 - Dérivé de pyrimidodiazépine servant d'inhibiteur sélectif de plk1 - Google Patents

Dérivé de pyrimidodiazépine servant d'inhibiteur sélectif de plk1 Download PDF

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Publication number
WO2022145989A1
WO2022145989A1 PCT/KR2021/020080 KR2021020080W WO2022145989A1 WO 2022145989 A1 WO2022145989 A1 WO 2022145989A1 KR 2021020080 W KR2021020080 W KR 2021020080W WO 2022145989 A1 WO2022145989 A1 WO 2022145989A1
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methyl
compound
mmol
difluoro
pyrimido
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Korean (ko)
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류수희
민임숙
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Uppthera Inc
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Uppthera Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel pyrimidodiazepine derivative compound, a method for preparing the same, and a use thereof for selectively inhibiting PLK1 (Polo-like kinase 1).
  • Polo-like kinase is a serine/threonine kinase family having a well-conserved N-terminal kinase enzyme domain, and is known to play a key role in cell cycle progression.
  • a total of four PLK family genes (PLK1, PLK2, PLK3 and PLK4) have been identified in mammals including humans, and these are the conserved NH 2 -terminal serine/threonine kinase domain and COOH- consisting of a polo-box. They share terminal regulatory domains (Schoffski, Oncologist 14.6 (2009), et al.).
  • PLK1 is a protein that plays a key role in various stages of the mitotic process and is known to be associated with a malignant prognosis and low overall survival rate in several types of carcinoma in humans (Li et al. Mini reviews in medicinal chemistry 13.14 (2013): 2014-2025.] et al.). Unlike normal tissues, PLK1 has been considered as one of the main targets of anticancer drugs due to its overexpression in a wide range of carcinomas (WO2003/020722; WO2004/076454; WO2006/021548; WO2009/042711, etc.)
  • the first-in-class prototype PLK1 inhibitor is BI-2536 developed by Boehringer Ingelheim, a dihydropteridinone derivative compound. It has been reported that BI-2536 induces mitotic arrest and apoptosis by disrupting spindle binding during cell division (Schoffski, Oncologist 14.6 (2009), et al.). Although positive results were reported as an anticancer agent in preclinical and early clinical trials, BI-2536 failed to prove sufficient efficacy in the phase 2 clinical trial, so development was stopped afterwards (Mross et al. British journal of cancer 107.2 (2012) ): 280-286.] etc.)
  • TAK-960 developed by Takeda is a 2-aryl pyrimidodiazepinone derivative compound in which the dihydropteridinone parent nucleus of BI-2536 is changed to a pyrimidodiazepinone parent nucleus (WO2009/042711, etc.).
  • TAK-960 developed as an anticancer drug, has also been reported to have limited efficacy in the clinical stage and limitations such as dose-limiting toxicity beyond the allowable value (Park et al. F1000Research 6 (2017), etc.).
  • PLK1 inhibitors developed so far, such as BI-2536 and TAK-960, are ATP-competitive inhibitors that inhibit the activity of PLK1 by competitively binding to the ATP-binding site of the serine/threonine kinase domain.
  • ATP competitive inhibitors have a problem in that they exhibit cross-activity to other kinases in addition to their target kinase enzyme, which is due to the well-conserved ATP-binding pocket structure of the kinase enzyme active site (Park et al. F1000Research 6 (2017) and Shakil, Shazi, et al (2019) et al.).
  • PLK Poly-like kinase
  • One object of the present invention is to provide a novel pyrimidodiazepine derivative compound.
  • Another object of the present invention is to provide a method for preparing the pyrimidodiazepine derivative compound.
  • Another object of the present invention is to provide a use of the pyrimidodiazepine derivative compound for inhibiting PLK1 (Polo-like kinase 1) or for preventing or treating a PLK1-related disease.
  • the present inventors confirmed that the selective inhibitory activity on PLK1 compared to similar kinases such as PLK2 and PLK3 in the novel pyrimidodiazepine derivative compound represented by Formula 1 described below or a pharmaceutically acceptable salt thereof is significantly improved and completed the present invention.
  • the present invention provides a novel pyrimidodiazepine derivative compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a use for selectively inhibiting PLK1 or for preventing or treating a PLK1-related disease using the same .
  • the present invention provides a novel pyrimidodiazepine derivative compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof.
  • R 1 is CF 3 , C 1-4 alkyl, C 3-6 cycloalkyl or —(C 1-4 alkylene)-OH;
  • X 1 is -CH 2 -, -CH(CH 3 )-, -CH(CH 2 CH 3 )-, -NH-, -N(CH 3 )- or -N(CH 2 CH 3 )-;
  • X 2 and X 3 are each independently hydrogen or C 1-3 alkyl
  • each one of the hydrogens in X 1 and X 2 is substituted with a single bond to form a nitrogen-containing 5- or 6-membered heterocyclyl ring;
  • each one of the hydrogens in X 1 and C 1-3 alkylene is substituted with a single bond to form a 5-membered or 6-membered ring;
  • each one of the hydrogens in R 3 and X 1 may be substituted with a single bond to form a 5-membered or 6-membered ring;
  • R 4 is hydrogen, C 1-10 alkyl or C 3-12 cycloalkyl.
  • the compound represented by Formula 1 is a compound represented by Formula 2 below.
  • R 1 is CF 3 , C 1-3 alkyl, C 3-5 cycloalkyl or —(C 1-3 alkylene)-OH;
  • X 1 is -CH 2 -, -CH(CH 3 )-, -CH(CH 2 CH 3 )-, -NH-, -N(CH 3 )- or -N(CH 2 CH 3 )-;
  • X 2 and X 3 are each independently C 1-3 alkyl
  • each one of the hydrogens in X 1 and X 2 is substituted with a single bond to form a nitrogen-containing 5- or 6-membered heterocyclyl ring;
  • each one of the hydrogens in X 1 and L 2 is substituted with a single bond to form a 5-membered or 6-membered ring;
  • each one of the hydrogens in R 3B and X 1 may be substituted with a single bond to form a 5-membered or 6-membered ring;
  • R 4 is C 3-6 alkyl or C 3-6 cycloalkyl.
  • the compound represented by Formula 2 is a compound represented by Formula 3-1 below.
  • R 1 is CF 3 , C 1-3 alkyl or —CH 2 CH 2 OH;
  • X A is CH or N
  • R 4 is isopropyl, cyclopropyl, cyclopentyl or cyclohexyl.
  • the compound represented by Formula 2 is a compound represented by Formula 3-2 below.
  • R 1 is CF 3 , C 1-3 alkyl or —CH 2 CH 2 OH;
  • X B is CH 2 or NH
  • R 4 is isopropyl, cyclopropyl, cyclopentyl or cyclohexyl.
  • the compound represented by Formula 2 is a compound represented by Formula 3-3 below.
  • R 1 is CF 3 , C 1-3 alkyl or —CH 2 CH 2 OH;
  • X C is CH or N
  • R 4 is isopropyl, cyclopropyl, cyclopentyl or cyclohexyl.
  • the compound represented by Formula 2 is a compound represented by Formula 3-4 below.
  • R 1 is CF 3 , C 1-3 alkyl or —CH 2 CH 2 OH;
  • X D is CH or N
  • R 4 is isopropyl, cyclopropyl, cyclopentyl or cyclohexyl.
  • the present invention provides a compound selected from the following compounds, or a pharmaceutically acceptable salt thereof:
  • the present invention provides a compound selected from compounds 1 to 15 provided in Examples to be described later, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt refers to any organic or inorganic acid addition salt that is a concentration having an effective action that is relatively non-toxic and harmless to a patient, and that side effects due to the salt do not reduce the beneficial efficacy of the compound represented by the formula (1).
  • the pharmaceutically acceptable salt may be hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid as an inorganic acid, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, Can be tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid or hydroiodic acid
  • the compounds of the present invention may be combined with other compound moieties of the functional structure at specific positions in the compounds of formula 1 by appropriate chemical modifications. For example, by linking a chemical moiety performing an additional pharmacological function in a cell through a chemical linker covalently bonded to R 2 or R 3 of the compound of Formula 1 of the present invention, a multifunctional compound utilizing PLK1 binding ability can be prepared. .
  • multifunctional compounds include, but are not limited to, PROTAC (Proteolysis targeting chimera) compounds.
  • the present invention provides a method for preparing a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • Formula 1 is as defined above.
  • the preparation method comprises the steps of (S1) converting a compound of Formula A to a compound of Formula B; and (S2) reacting a compound of Formula B with a compound of Formula C to obtain a compound of Formula 1;
  • R 1 , R 2 , R 3 and R 4 are as described in Formula 1 above.
  • the S1 reaction is carried out in Examples (Step 2 of Example 1, Step 2 of Example 2, Step 3 of Example 3, Step 6 of Example 4, Step 6 of Example 5, Step 5 of Example 6, Step 6 of Example 7, Step 4 of Example 9, Step 2 of Example 11, Step 2 of Example 13, Step 3 of Example 14, Step 3) of Example 15 and known With reference to literature and the like, it can be easily carried out by those skilled in the art of organic synthesis.
  • a reactant having an obvious variant of R 2 in the compound of formula A as a substituent may be used as an alternative (step 1 of Example 8) to 2, step 1 to step 2 of Example 10, etc.).
  • the S2 reaction is an example (Step 3 of Example 1, Step 3 of Example 2, Step 4 of Example 3, Step 7 of Example 4, Step 7 of Example 5, and Example 6) to be described later in the S2 reaction.
  • Step 6 Step 7 and Step 8 of Example 7, Step 3 of Example 8, Step 5 of Example 9, Step 3 of Example 10, Step 3 of Example 11, Step 8 of Example 12, Example With reference to step 3 of 13, step 4 of Example 14, step 4 of Example 15) and known literature, those skilled in the art of organic synthesis can easily carry out the process.
  • the compound of formula A used in the reaction S1 has a nitrobenzene structure, -OR 1 is at the 2nd position of the benzene ring based on the nitro group substitution position, R 2 is at the 5th position, R 2 is at the 3rd or 4th position 3 Characterizes this substituted structure.
  • the method of substituting —OR 1 at the 2-position of the nitrobenzene ring of Formula A is described in the following Examples (Step 1 of Example 3, Step 1 of Example 4, Step 1 and Step 2 of Example 5) , Step 1 of Example 6, Step 1) of Example 7 can be easily carried out by those skilled in the art of organic synthesis with reference to the manufacturing method.
  • the method of substituting R 2 at the 5-position of the nitrobenzene ring of Formula A is described in the following Examples (Step 1 of Example 1, Step 1 of Example 2, Step 2 of Example 3, Example 4) Step 3 of Example 5, Step 3 of Example 6, Step 2 of Example 7, Steps 1 to 2 of Example 8, Steps 1 to 3 of Example 9, Step of Example 10 1 to 2, Step 1 of Example 11, Step 1 of Example 13, Step 1 to Step 2 of Example 14, Step 1 to Step 2) of Example 15) Technicians can easily perform it.
  • the method of substituting R 3 at the 3 or 4 position of the nitrobenzene ring of Formula (A) is described in the following Examples (Step 2 of Example 4, Steps 4 to 5 of Example 4, Steps of Example 5) 4 to 5, step 2 of Example 6, step 3 to step 5) of Example 7) can be easily carried out by those skilled in the art of organic synthesis.
  • the present invention provides the use of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for selectively inhibiting PLK1.
  • Formula 1 is as defined above.
  • PLK1 is a serine/threonine protein kinase belonging to the Polo-like kinase (PLK) family, and is known to play a key role in various stages of mitosis (NCBI Reference Sequence for human PLK1: NP_005021) see .2, etc.).
  • the compound of the present invention is characterized by remarkably improved selective binding and inhibitory ability to PLK1 compared to other kinases, particularly PLK2 and PLK3, which is due to the characteristic structure of the compound represented by Formula 1.
  • the terminal nitrogen atom of the R 2 substituent represented by 1-methylpiperazine, etc. in the compound represented by Formula 1 of the present invention eg, -LX 1 -(C) represented by the R 2 substituent in Formula 1 above 1-3 alkylene)-NX 2 X 3 nitrogen atom
  • -LX 1 -(C) represented by the R 2 substituent in Formula 1 above 1-3 alkylene)-NX 2 X 3 nitrogen atom is presumed to form a selective hydrogen bond with the GLU140 amino acid residue present in PLK1.
  • histidine is located at the corresponding position of GLU140 in PLK1, so it is presumed that the above interaction will not occur.
  • the compounds of the present invention may further enhance PLK1 selective inhibitory activity by forming interactions with amino acid residues in PLK1 such as GLU69 and CYS133 (additionally ARG57 and ARG134). Due to such structural features, the compound of the present invention can significantly improve selective PLK1 inhibitory activity compared to similar ATP-competitive kinases such as PLK2 and PLK3.
  • a PLK1-related disease refers to any disease or condition that can be treated, alleviated, delayed, inhibited or prevented from selective inhibition of PLK1.
  • the PLK1-associated disease is any cancer (eg, solid cancer or hematologic cancer) that may exhibit prophylactic or therapeutic efficacy due to inhibition of PLK1 activity.
  • the cancer is squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung, peritoneal cancer, skin cancer, skin or intraocular melanoma, rectal cancer, perianal cancer, esophageal cancer, small intestine cancer, endocrine cancer Adenocarcinoma, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, chronic or acute leukemia, lymphocytic lymphoma, hepatocellular carcinoma, gastrointestinal cancer, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver tumor, breast cancer, colon cancer , colon cancer, endometrial or uterine cancer
  • a pharmaceutical comprising the compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof
  • the pharmaceutical composition may be usefully used for the prevention or treatment of a PLK1-related disease (eg, cancer).
  • a PLK1-related disease eg, cancer
  • the present invention significantly improved the selective PLK1 inhibitory activity against PLK2 and 3 compared to Comparative Compounds 1 and 2 (BI-2536 and TAK-960), which are conventional PLK1 inhibitory compounds.
  • it can be usefully utilized as an anticancer agent that significantly improved cancer-specific anticancer effects, etc. (Table 3).
  • the pharmaceutical composition of the present invention may further include one or more pharmaceutically acceptable carriers in addition to the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for administration.
  • a pharmaceutically acceptable carrier may be used in a mixture of saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components, and if necessary, an antioxidant, buffer , and other conventional additives such as a bacteriostatic agent may be added.
  • compositions of the present invention may be a patch, solution, pill, capsule, granule, tablet, suppository, and the like.
  • formulations may be prepared by a conventional method used for formulation in the art or a method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA, and may be formulated into various formulations according to each disease or component. can
  • the pharmaceutical composition of the present invention may be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or topically) according to a desired method, and the dosage may vary depending on the patient's weight, age, sex, and health condition. , diet, administration time, administration method, excretion rate and the severity of the disease, etc., the range varies.
  • the pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar efficacy in addition to the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • One embodiment of the present invention is a method for inhibiting PLK1 by administering a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a mammal including a human.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is administered to a sample in vitro or ex vivo, or administered to a biological tissue other than a human.
  • the sample may be a cell, a cell culture, a body fluid or tissue of a mammal including a human, but is not limited thereto.
  • Another embodiment of the present invention provides a method for preventing or treating a PLK1-related disease (eg, cancer) comprising administering to a human a therapeutically effective amount of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to be.
  • a PLK1-related disease eg, cancer
  • the pyrimidodiazepine derivative compound of the present invention has significantly improved the selective inhibitory effect of PLK1 compared to the conventional PLK1 inhibitor, it can be usefully used for the prevention or treatment of PLK1-related diseases.
  • LCMS data were recorded with a Shimadzu LCMS-2020 equipped with an electron spray ionization apparatus.
  • 0.0375 % TFA in water (solvent A) and 0.01875 % TFA in acetonitrile (solvent B) or 0.025% NH 3 .H 2 O in water (solvent A) and acetonitrile (solvent B) were used as mobile phases.
  • Kinetex EVO C18 (2.1*30)mm, 5um was used as a column.
  • HPLC was performed using Shimadzu LC-20AB or Agilent 1200/G6410B or Agilent 1290, with 0.0375 % TFA in water (solvent A) and 0.01875 % TFA in acetonitrile (solvent B) or 0.025% NH 3 H 2 O in water ( Solvent A) and acetonitrile (solvent B) were used as mobile phases.
  • solvent A 0.0375 % TFA in water
  • solvent B 0.01875 % TFA in acetonitrile
  • solvent B 0.025% NH 3 H 2 O in water
  • Solvent A acetonitrile
  • the pH of the H 2 O layer was adjusted to about 10 with solid K 2 CO 3 and extracted with DCM (50 mL ⁇ 2). The combined DCM layers were dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo. The title compound (680 mg, 3.07 mmol, 77.21% yield) was obtained as a black solid, which was used in the next step without further purification.
  • Step 3 9-Cyclopentyl-7,7-difluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-8,9 Synthesis of -dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (Compound 1)
  • Step 3 9-Cyclopentyl-7,7-difluoro-2-((2-methoxy-5-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-5-methyl- Synthesis of 8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (Compound 2)
  • Step 3 Synthesis of 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-(4-methylpiperazin-1-yl)aniline (4)
  • Step 4 9-Cyclopentyl-7,7-difluoro-2-((2-(2-hydroxyethoxy)-5-(4-methylpiperazin-1-yl)phenyl)amino)-5 Synthesis of -methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (Compound 3)
  • Step 4 Synthesis of 5-methoxy-2-(4-methylpiperazin-1-yl)-4-nitrobenzoic acid (5)
  • the reaction mixture was filtered and the filtrate was prep-HPLC (column: Waters Xbridge C 18 150*50 mm* 10um;mobile phase: [water(10 mM NH 4 HCO 3 )-ACN];B%: 5%-35% , 10 min).
  • the title compound (200 mg, 648.65 ⁇ mol, 22.29% yield) was obtained as a brown solid.
  • Step 6 Synthesis of 4-amino-5-methoxy-N-methyl-2-(4-methylpiperazin-1-yl)benzamide (7).
  • Step 7 4-[(9-cyclopentyl-7, 7-difluoro-5-methyl-6-oxo-8H-pyrimido[4, 5-b][1, 4]diazepin-2-yl Synthesis of amino]-5-methoxy-N-methyl-2-(4-methylpiperazin-1-yl)benzamide (compound 4)
  • the reaction mixture was filtered and Prep-HPLC (column: Waters Xbridge C 18 150*50 mm* 10um; mobile phase: [water(10 mM NH 4 HCO 3 )-ACN];B%: 32%-62%, 11 min ) was purified.
  • the title compound (66.6 mg, 112.07 ⁇ mol, 15.60% yield, 94% purity) was obtained as a white solid.
  • Step 3 Synthesis of methyl 2-methoxy-5-(4-methylpiperazin-1-yl)-3-nitrobenzoate (4).
  • Methyl 5-bromo-2-methoxy-3-nitrobenzoate (1.3 g, 4.48 mmol), 1-methylpiperazine (897.79 mg, 8.96 mmol, 994.23 ⁇ L) in dioxane (13 mL), Xantphos (259.32) mg, 448.17 ⁇ mol), Cs 2 CO 3 (2.92 g, 8.96 mmol) and Pd 2 (dba) 3 (205.20 mg, 224.09 ⁇ mol) mixture was heated at 100° C. for 16 h. As a result of LCMS measurement, the starting material was completely consumed, and the target mass was detected.
  • Step 7 3-((9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b] Synthesis of [1,4]diazepin-2-yl)amino)-2-methoxy-N-methyl-5-(4-methylpiperazin-1-yl)benzamide (compound 5)
  • Product B (172 mg) was prep-HPLC (column: Phenomenex Gemini-NX C 18 75*30mm*3um; mobile phase: [water (10mM NH 4 HCO 3 ) -ACN]; B%: 22%-52%, 8 min) to give product D.
  • Product C and product D were combined by lyophilization to give 87 mg of product E, the purity of product E (87 mg) was 86% by HPLC and LCMS.
  • Product E (87 mg) was prep-HPLC (column: Phenomenex Gemini-NX C 18 75*30mm*3um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 22%-52 %, 11.5 min) to give product F (56 mg), the purity of product F (56 mg) was 84% by LCMS and HPLC.
  • Product F (56 mg) was prep-HPLC (column: Shim-pack C 18 150*25*10um;mobile phase: [water (0.225%FA)-ACN];B%: 11%-31%, 10min) Repurification gave the title compound (26.1 mg, 45.79 ⁇ mol, 9.67% yield, 98% purity) as a white solid.
  • Step 2 Synthesis of methyl 5-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-2-fluoro-4-nitrobenzoate (3).
  • the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0-15% Ethyl acetate/Petroleum Ether gradient @ 100 mL/min). did.
  • the title compound (5.4 g, 14.46 mmol, 61.87% yield) was obtained as a yellow solid.
  • Step 6 4-[(9-cyclopentyl-7, 7-difluoro-5-methyl-6-oxo-8H-pyrimido[4, 5-b][1, 4]diazepin-2-yl Synthesis of amino]-5-(2-hydroxyethoxy)-N-methyl-2-(4-methylpiperazin-1-yl)benzamide (Compound 6)
  • Step 1 Synthesis of methyl 5-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3-nitrobenzoate (3)
  • Step 2 Synthesis of methyl 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-(4-methylpiperazin-1-yl)-3-nitrobenzoate (4).
  • Step 4 Synthesis of 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-(4-methylpiperazin-1-yl)-3-nitrobenzoic acid (6)
  • Step 5 Synthesis of 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-N-methyl-5-(4-methylpiperazin-1-yl)-3-nitrobenzamide (7).
  • Step 6 Synthesis of 3-amino-2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-N-methyl-5-(4-methylpiperazin-1-yl)benzamide (8).
  • Step 7 2-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-3-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7 ,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-methyl-5-(4-methylpiperazin-1-yl) ) Synthesis of benzamide (10)
  • Product A 120 mg was prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (10mM NH 4 HCO 3 ) -ACN]; B%: 56%-86%, 10min) Purification gave product C. Purification of product B (224 mg) by prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water (10mM NH 4 HCO 3 )-ACN]; B%: 56%-86%, 10 min) to obtain product D. Product C and Product D were combined to give the title compound (71 mg, 85.86 ⁇ mol, 27.19% yield, 85% purity) as a yellow solid.
  • Step 8 3-((9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b] of [1,4]diazepin-2-yl)amino)-2-(2-hydroxyethoxy)-N-methyl-5-(4-methylpiperazin-1-yl)benzamide (Compound 7) synthesis
  • the mixture was stirred at 90 °C for 1 h. As a result of LCMS measurement, the starting material was completely consumed, and 85% of the target mass was detected.
  • the reaction mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; X g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate/Petroleum ether gradient @ 100 mL/min ). The title compound (774 mg, 3.09 mmol, 71.61% yield, 99% purity) was obtained as a yellow solid.
  • Step 3 9-cyclopentyl-7,7-difluoro-2-((2-methoxy-5-(1-methylpiperidin-4-yl)phenyl)amino)-5-methyl-8, Synthesis of 9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (compound 8)
  • Step 5 9-Cyclopentyl-7,7-difluoro-2-((2-methoxy-5-((1-methylpiperidin-4-yl)methyl)phenyl)amino)-5-methyl Synthesis of -8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (Compound 9)
  • Step 1 Synthesis of 3-(4-methoxy-3-nitrophenyl)-N,N-dimethylprop-2-yn-1-amine (3)
  • Step 3 9-Cyclopentyl-2-((5-(3-(dimethylamino)propyl)-2-methoxyphenyl)amino)-7,7-difluoro-5-methyl-8,9-di Synthesis of hydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (compound 10)
  • Step 2 Synthesis of 1-(3-amino-4-methoxyphenyl)-N,N-dimethylpiperidin-4-amine (4)
  • Step 3 2-((5-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)-7,7-difluoro-9-isopropyl-5-methyl Synthesis of -5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (Compound 11)
  • prep-HPLC column: Phenomenex Synergi C18 150*25 mm* 10um; mobile phase: [H 2 O (0.1% TFA) -ACN]; B%: 12% - 42%, 10 min
  • prep-HPLC columnumn: Waters Xbridge 150*25 mm* 5um; mobile phase: [H 2 O (10 mM NH 4 HCO 3 ) - ACN]; B%: 35% - 65%, 10 min
  • freeze Drying gave the title compound (33.3 mg, 62.16 ⁇ mol, 18.07% yield, 94% purity) as a white solid.
  • Step 2 Synthesis of N-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-N-benzylpropan-2-amine (5)
  • the aqueous phase was extracted with EA (100 mL), and the combined organic phases were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • the title compound (40.4 g) was obtained as a colorless gum and used in the next step without further purification.
  • Step 3 Synthesis of ethyl 3-(benzyl(isopropyl)amino)-2,2-difluoropropanoate (7)
  • TMSCl 39.14 g, 360.24 mmol, 45.72 mL
  • Zn 23.56 g, 360.24 mmol
  • THF 150 mL
  • ethyl 2-bromo-2,2-difluoroacetate 58.50 g, 288.19 mmol, 37.02 mL
  • Step 4 Synthesis of ethyl 2,2-difluoro-3- (isopropylamino) propanoate (8)
  • Step 5 Synthesis of ethyl 3-((2-chloro-5-nitropyrimidin-4-yl)(isopropyl)amino)-2,2-difluoropropanoate (10).
  • the aqueous phase was extracted with EA (300 mL x 2), and the combined organic phases were washed with NaHCO 3 solution (200 mL x 2), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • the residue was dissolved with MTBE (40 mL) for 10 minutes and the suspension was filtered.
  • the solid portion was washed with MTBE (20 mL) and concentrated under reduced pressure to obtain the title compound (12.8 g, 46.26 mmol, 73.83% yield) as a white solid.
  • Step 8 7,7-difluoro-9-isopropyl-2-((2-methoxy-5-(1-methylpiperidin-4-yl)phenyl)amino)-5-methyl-5, Synthesis of 7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (Compound 12)
  • Step 3 7,7-Difluoro-9-isopropyl-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-5,7 Synthesis of ,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (Compound 13)
  • prep-HPLC column: Phenomenex Synergi C18 150*25 mm* 10um; mobile phase: [H 2 O (0.1% TFA) -ACN]; B%: 12% - 42%, 10 min
  • prep-HPLC columnumn: Waters Xbridge 150*25 mm* 5um; mobile phase: [H 2 O (10 mM NH 4 HCO 3 ) -ACN]; B%: 40% - 70%, 10 min) and freeze-drying to give the title compound (18.5 mg, 38.13 ⁇ mol, 11.08% yield, 98% purity) as a white solid.
  • Step 3 Synthesis of 1-(6-amino-5-methoxyindolin-1-yl)-2-(dimethylamino)ethan-1-one (4)
  • Step 4 9-Cyclopentyl-2-((1-(dimethylglycyl)-5-methoxyindolin-6-yl)amino)-7,7-difluoro-5-methyl-5,7,8 Synthesis of ,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (Compound 14)
  • prep-HPLC column: Phenomenex Synergi C18 150*25 mm* 10um; mobile phase: [H 2 O (0.1%TFA) - ACN]; B%: 26%-56%, 10 min
  • prep-HPLC columnumn: Waters Xbridge 150*25 mm* 5um; mobile phase: [H 2 O (10 mM NH 4 HCO 3 )-ACN]; B%: 45% - 75%, 10 min) and freeze Drying gave the title compound (21.2 mg, 39.63 ⁇ mol, 12.55% yield, 99% purity) as a white solid.
  • Step 2 Synthesis of 1-(2-(dimethylamino)ethyl)-5-methoxy-6-nitroindolin-2-one (4)
  • Step 3 Synthesis of 6-amino-1-(2-(dimethylamino)ethyl)-5-methoxyindolin-2-one (5)
  • the product was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25 mm* 10um; mobile phase: [H 2 O (0.1% TFA) -CAN]; B%: 1% - 20%, 10 min) and then frozen Drying gave the title compound (120 mg, 457.27 ⁇ mol, 42.57% yield, 95% purity) as a brown oil, which was used in the next step without further purification.
  • Step 4 9-Cyclopentyl-2-((1-(2-(dimethylamino)ethyl)-5-methoxy-2-oxoindolin-6-yl)amino)-7,7-difluoro- Synthesis of 5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (Compound 15)
  • Comparative Compounds 1 and 2 were selected as Comparative Compounds 1 and 2, respectively.
  • the structures of Comparative Compounds 1 and 2 are summarized in the table below.
  • a kinase assay was performed. For this, compounds 1 to 15 were reacted with PLK1, PLK2 and PLK3 to measure kinase activity inhibitory ability, and IC 50 values were calculated. 8 mM MOPS pH 7.0, 0.2 mM EDTA, and 10 mM Mg acetate were used as the reaction buffer, and all test articles were reacted in the reaction buffer.
  • the active enzymes PLK1, PLK2 (Snk), and PLK3 (expressed and purified as a recombinant protein through the SF9 cell line) were added to the wells containing the compound, respectively. added to 1.25 mg/mL of casein was added to the wells supplemented with PLK1 and 2 mg/mL of casein was added to the wells supplemented with PLK2 and PLK3, respectively.
  • 10 ⁇ M [gamma- 32 P]-ATP was added and reacted at room temperature for 40 minutes. Thereafter, phosphoric acid was added to terminate the reaction.
  • kinase activity was calculated as (average of sample counts minus average of blank counts)/(average of control counts), which represents the percentile of kinase activity relative to DMSO control values.
  • IC 50 values were calculated using XLFit version 5.3 (ID Business Solutions). A sigmoidal dose-response (variable slope) curve was created based on the average of the results for each test concentration using nonlinear regression analysis. As a result, IC 50 values for the PLK1, PLK2 and PLK3 kinase enzyme activities described in the table below were obtained.
  • the novel compounds presented in the present invention exhibit PLK1 inhibitory activity at the same level as Comparative Compound 1 (BI-2536) and Comparative Compound 2 (TAK-960), which are conventionally known as PLK1 inhibitors, whereas PLK2 and PLK3 It showed almost no inhibitory activity, indicating that the selective PLK1 inhibitory activity was remarkably improved.

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Abstract

La présente invention concerne : un nouveau composé dérivé de pyrimidodiazépine représenté par la formule 1 ou un sel pharmaceutiquement acceptable de celui-ci ; leur procédé de préparation ; et leurs utilisations pour inhiber de manière sélective PLK1 ou prévenir ou traiter des maladies associées à PLK1. Le composé dérivé de pyrimidodiazépine selon la présente invention a un effet inhibiteur sélectif amélioré de manière significative sur PLK1 par comparaison avec des inhibiteurs de PLK1 existants, et peut ainsi être utilisé de manière efficace pour prévenir ou traiter des maladies associées à PLK1.
PCT/KR2021/020080 2020-12-31 2021-12-28 Dérivé de pyrimidodiazépine servant d'inhibiteur sélectif de plk1 Ceased WO2022145989A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20090038895A (ko) * 2006-07-06 2009-04-21 아스트라제네카 아베 융합된 피리미도 화합물
KR20090119913A (ko) * 2007-03-22 2009-11-20 에프. 호프만-라 로슈 아게 Ｐｌｋ１ 저해제로서 유용한 치환된 피리미도디아제핀
WO2009153197A1 (fr) * 2008-06-18 2009-12-23 F. Hoffmann-La Roche Ag Pyrimidodiazépines à substitution halogéno en tant qu’inhibiteurs de plkl
WO2010080712A2 (fr) * 2009-01-06 2010-07-15 Dana Farber Cancer Institute Composés pyrimido-diazépinone d'échafaudage de kinase et procédés de traitement de troubles
KR20140097440A (ko) * 2007-09-25 2014-08-06 다케다 야쿠힌 고교 가부시키가이샤 폴로형 키나아제 억제제

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20090038895A (ko) * 2006-07-06 2009-04-21 아스트라제네카 아베 융합된 피리미도 화합물
KR20090119913A (ko) * 2007-03-22 2009-11-20 에프. 호프만-라 로슈 아게 Ｐｌｋ１ 저해제로서 유용한 치환된 피리미도디아제핀
KR20140097440A (ko) * 2007-09-25 2014-08-06 다케다 야쿠힌 고교 가부시키가이샤 폴로형 키나아제 억제제
WO2009153197A1 (fr) * 2008-06-18 2009-12-23 F. Hoffmann-La Roche Ag Pyrimidodiazépines à substitution halogéno en tant qu’inhibiteurs de plkl
WO2010080712A2 (fr) * 2009-01-06 2010-07-15 Dana Farber Cancer Institute Composés pyrimido-diazépinone d'échafaudage de kinase et procédés de traitement de troubles

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